A high performance cryogenic probe will be integrated with a 500 MHz nuclear magnetic resonance (NMR) spectrometer system, which is currently housed in the Protein NMR Facility of the Structural Biology Program at the Mount Sinai School of Medicine. This recently developed instrument represents a major break-through technology in NMR spectroscopy. It offers significant sensitivity enhancement for up to 4- fold, which should have tremendous impacts on contributions of NMR spectroscopy to Structural Biology. Particularly, this new cryogenic probe makes it possible to apply high-resolution NMR techniques to study he detailed structure and function relationships of large and dynamic proteins, protein-protein, and protein-DNA complexes that have low solubility in solution, such as membrane associated proteins and receptors. Specifically, this new instrument will greatly facilitate many ongoing NIH funded studies on the Mount Sinai campus, that focus on the structural basis of molecular mechanisms of protein-protein or protein-DNA interactions and enzymatic regulation of a wide range of biological systems. These study include (1) Structure and function of proteins in signal transduction and chromatin-mediated transcriptional regulation; (2) Molecular mechanism of cadherin-mediated cell adhesion; (3) The Function of the leukemia protein PML and molecular recognition of RING domains; (4) Structural basis for neurotrophic receptor interactions with the SNT signal transducer; (5) Molecular mechanisms of G protein-mediated activation of potassium channels; and (6) Molecular basis of transporters and receptors.